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Cysteine Acquisition and Utilization in Lung Adenocarcinoma

Award Number: R01CA309659
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/12/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Cysteine Acquisition and Utilization in Lung Adenocarcinoma - PROJECT SUMMARY Cysteine-derived molecules are crucial for cancer cell survival and proliferation because of their sulfur moiety, which facilitates diverse functions, including enzyme catalysis, energy transfer, and redox metabolism. This project aims to challenge the current paradigm that tumor cells primarily obtain cysteine through xCT-mediated cystine import. Our preliminary data reveal that the tumor microenvironment is highly reduced, with cysteine available predominantly in its reduced form and millimolar concentrations of glutathione (GSH) that maintain cysteine in this state. This proposal will investigate three critical aspects of tumor cysteine metabolism: (1) the origins and mechanisms regulating cysteine availability in the tumor microenvironment, with focus on GSH- mediated copper chelation and cystine reduction; (2) the identification and characterization of cysteine transporters and their context-dependent requirements across different tumor regions; and (3) how the availability of reduced cysteine versus oxidized cystine fundamentally reprograms cellular metabolism by bypassing xCT-mediated cystine import, thereby preserving cellular NADPH and glutamate pools. We will leverage innovative approaches including quantitative metabolomics with optimized derivatization methods, in vivo stable isotope tracing, MALDI imaging mass spectrometry, and specialized culture systems that recapitulate the unique metabolite composition of the tumor microenvironment. Understanding how the reducing tumor microenvironment influences cysteine availability and utilization is highly relevant to cancer research, as it reveals the true metabolic dependencies of cancer cells in their native context. This work will identify novel therapeutic targets that better reflect in vivo tumor metabolism, potentially leading to more effective treatments for lung adenocarcinoma and other cancers where cysteine metabolism is dysregulated.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $687,593 )
2026	2026	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	1	5/13/2026	NEW	$687,593
														Subtotal = $687,593

Grand Total All Awards = $687,593

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Cysteine Acquisition and Utilization in Lung Adenocarcinoma

Award Number: R01CA309659

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/12/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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